The basic goal of our laboratory continues to be the search for exploitable differences between normal and cancer cells. Our major study system includes the four major types of human leukemic cells, normal leukocytes, lymphocytes, and lymphoblastoid cell lines of human origin. We have recently instituted a comprehensive study of leukemia cell metabolism concentrating on the comparative effects of lipid soluble 5-arylpyrimidine antifolates and methotrexate on relevant metabolic pathways in intact cells. In this study we are examining the mechanisms of differential response to these drugs within and between leukemic types and of resistance to these drugs as it occurs both in unselected patients and through various courses of chemotherapy with homologous or heterologous drugs. We are also continuing our study of DNA polymerases of leukemic cells with the primary focus on comparing the polymerases and the mode of DNA synthesis in acute and chronic granulocytic leukemic cells. In this study we hope to explain the anomalous observation that, whereas AGL cells have a high amount of polymerase activity, they exhibit low levels of DNA synthesis when compared to CGL cells which have low DNA polymerase activity and a high level of DNA synthesis.